Nephrotoxicants

1. Nephrotoxicants

2. Oxalate toxicosis -1 • Beta vulagaris (beet) • - tops high in oxalates • Chenopodium album (lamb’s quarters) • - both oxalates and nitrates • Halogeton glomeratus - arid, high saline soils • - oxalate peak in fall, persists through winter • Rheum rhaponticum (rhubarb) • - leaves contain anthroquinone glycosides, too • Sarcobatus vermiculatus(greasewood) • - western range, oxalates all parts, • more [ ]’d as plant matures Halogeton Sarcobatus

3. Oxalate toxicosis - 2 • Soluble oxalates plus serum calcium calcium oxalate • Ionized calcium depleted functional hypcalcemia • Crystallization in renal tubulesfatal renal tubular toxicosis • One-time consumption sufficient to cause toxicosis Clinical signs • muscle twitching, mild seizures, prostration, death possible • oligura, depression, vomiting, azotemia, depression, hyperkalemia, cardiac failure • if don’t die, may develop chronic tubular nephrosis with polyuria and hyposthenuria Treatment • limewater (calcium hydroxide) to ppt. oxalate in intestinal tract

4. Cholecalciferol (vitamin D) toxicosis • Cestrum diurnum(night-blooming jessamine) • S and SE UStropical and subtropical US • Solanum malacoxylon • HI and S. America Dx - clinical and lab • vitamin D excess  hypercalcemia  soft tissue mineralization, renal tubular necrosis • depression, anorexia,vomiting, PU/PD, azotemia • serum calcium >2mg/dl

5. Quercus spp.(oak) • polyhydroxyphenolic -gallotannin, in both leaves and acorns • common in cattle and calves, less sheep & horses Clinical signs- • anorexia, dullness, rumen atony, constipation, feces dark w/mucus film (or tarry stool) • weakness, prostrate 3-7 d post-exposure, mortality may be high • icterus, hematuria, dehydration, polyuria, hyposthenuria • abortion

6. Quercus spp.(oak) Treatment- • 10-15% calcium hydroxide in grain to aid precipitation of oak tannins and reduce mortality in cattle Lesions- • gastroenteritis, ascites, hydrothorax • subserosal petechial or ecchymotic hemorrhages over surface of gi tract • gelatinous blood-tinged edema around kidneys, which are enlarged, pale, hemorrhagic • coagulative necrosis of proximal convoluted tubules

7. Amaranthus retroflexus (redroot pigweed) • moist disturbed soils, U.S. • accumulate nitrates and oxalates, but these don’t cause toxicosis Clinical signs (swine) - • weakness, trembling, incoordination, knuckling of pastern joints, paralysis of hind limbs, coma, death • elevated BUN, creatinine, serum K, bradycardia • survivors may have chronic interstitial fibrosis in kidneys but appear clinically normal (Signs in cattle like oak poisoning)

8. Hemerocallus, Lilium (daylily, lilies) • cultivated, escapees • assoc. w/renal tubular necrosis in cats • all parts nephrotoxic Clinical signs - • anorexia, depression, anuria • acute renal tubular necrosis • ingestion is medical emergency!

9. Cardiotoxicants

10. Andromedotoxicosis (grayanotoxicosis) • Kalmia (laurel, lambkill, calfkill) • - threat to browsing animals • Rhododendron (rhododendron, azalea) • - wild and cultivated • Pieris japonica (Japanese pieris)

11. Andromedotoxicosis - 2 • diterpenoid compounds modify Na channels, leading to prolonged depolarization and excitation • favors Ca movement into cells and positive inotropic effect Clinical signs • salivation, burning sensation in mouth, followed by emesis, diarrhea, muscular weakness, impaired vision • bradycardia, hypotension d.t. vasodilation, av block Treatment • atropine • isoproterenol or sodium channel blockers (e.g., quinidine)

12. Digitalis glycoside poisoning Apocynum (dogbane, hemp) Convallaria majalis (lily-of-the-valley) - toxin in flowers, leaves, seeds, not berries • Digitalis purpurea (foxglove) - digitalis glycosides all parts  Nerium oleander (oleander)- highly toxic, few oz. kills horse

13. Cardiac Glycoside Poisoning - 2 • conduction block and eventual asystole • toxins readily absorbed, enterohepatic recycling Clinical signs • initially gi - vomiting, abdominal pain, moderate to severe diarrhea (sometimes hemorrhagic) • bradycardia, arrhythmias, ventricular premature systoles, paroxysmal tachycardia, complete heart block, asystole • depression and coma d.t. cardiac insuffienciency Treatment • monitor and treat hyperkalemia • phenytoin may assist av conduction and  heart rate • antidigitalis antibody fragments for severe toxicosis

14. Digitalis-like Glycoside Poisoning - 2 • Aconitum napellum (monkshood) • aconitine and related alkaloids • toxin in entire plant Clinical signs • oral and pharyngeal inflammation, salivation, nausea, emesis, blurred vision • hypotension, cardiac arrhythmias, weakness prior to death Treatment • as for cardioactive glycosides • Asclepias (milkweed) - see neurotoxicants

15. Taxus cuspidata, T. baccata(Japanese yew, English yew) • taxine alkaloids (A and B) inhibit depolarization in heart • whole plant except red aril (fruit) is highly toxic • 6-8 oz. kills horse or cow Clinical signs • trembling, muscle weakness, dyspnea, collapse • arrhythmia, bradycardia, diastolic heart Treatment • atropine early may help

16. Zygademus (death camas) • Great Plains and Rocky Mtn. states • steroidal alakloid - zygadenine or zygacine • all parts of the plant • one of first green plants available in spring Clinical signs • salivation, nausea, vomiting, rapid pulse, stiffness, trembling, ataxia, weakness, recumbency, coma, death

17. Toxicants that alter peripheral circulation

18. Berteroa incana(hoary alyssum) • central U.S., pastures, hay fields, waste areas • toxic principal unknown Clinical signs • moderate to severe laminitis • edema of lower limbs

19. Festuca arundinacea (Kentucky 31 tall fescue) • major forage grass in SE U.S. • endophytic fungus Acremonium coenophialum • ergopeptide alkaloids (esp. ergovaline) found in leaves and seeds • can purchase endophyte-free strains • 3 clinical syndromes • no treatment except for pain

20. Festuca arundinacea (Kentucky 31 tall fescue) Fescue foot • dry gangrene of extremities (feet, tail, ears) • cold weather accentuates severity • lameness often begins in rear limbs in cattle Bovine fat necrosis • large masses of hardened fat in abdomen • when pure stands heavily fertilized “Summer syndrome” or “summer slump” - most economically damaging - lower weight gains, reduced milk production, heat intolerance -  postpartum interval,  pregancy rates

21. Juglans nigra (black walnut) • shavings or sawdust occasionally used as animal bedding • horses at greatest risk • toxic principle unknown Clinical signs • w/in 24 hrs of exposure, rapid onset of laminitis, digital pulse, distal edema of the limbs, polypnea, elevated temperature • necrosis of the dorsal laminae may occur

22. Pulmonary toxicants

23. Plant sources of pulmonary toxicants • Brassica (rape, canola) • glucosinolates hydrolyzed to isothiocyantes in stomach or rumen • Ipomea batata (sweet potato) • Fusarium solani produces ipomeanol, mycotoxin causing acute pulmonary emphysema in cattle • Perilla frutescens (purple mint, beefsteak plant) • Perilla ketone similar to ipomeanol

24. Pulmonary toxicants - 2 • Clinical signs • dyspnea, cyanosis from anoxia • cattle extend head, open-mouth breathe • disorientation, belligerance, recumbency, death within a few hours to 1-2 days • Lesions • massive pulmonary emphysema • air may infiltrate subcutaneous space voer thorax and behind scapulae • Type I cells absent or necrotic, replacement by type II cells gives lung appearance of “adenomatosis”

25. Plants that affect the blood Hematopoeitic depression Hemolysis Hemorrhage Methemoglobinemia Cyanide toxicosis

26. Pteridium aquilinum (bracken fern) • forested areas of N. U.S. • lactone - ptaquiloside responsible for effects on blood • all parts are toxic • thiaminase activity in horses Clinical signs (cattle) - aplastic anemia, granulocytopenia, thrombocytopenia; urinary bladder neoplasms w/chronic exposure • Dl batyl alcohol limited value Clinical signs (horses) - thiamine deficiency, ataxia, weakness, paralysis, NO blood effects • thiamine injections may help Prognosis poor in advanced cases

27. Acer rubrum (red maple) • natural in East, cultivated elsewhere • toxic principle unknown • causes acute hemolysis in horses • fresh, wilted, dried leaves Clinical signs • depression, icterus, anemia, hemoglobinemia, hemoglobinuria • polypnea, tachycardia, cyanosis may be present • low PCV, mild methemoglobinemia, Heinz bodies, hyperbilirubinemia, occ. increased • Whole blood transfusion may be lifesaving.

28. Allium spp.(onions, garlic) • N-propyl disulfide denatures hemoglobin • toxicant present in “bulb” • cattle more susceptible than other species; dogs, horses, rabbits, too. Clinical signs • weakness, polypnea, icterus, hemoglobinuria, cyanosis • Whole blood transfusion may be lifesaving

29. Lespedeza sericea, Melilotus officinalis and M. alba (sweetclover) • legume cover or forage crops • coumarin glycosides dimerized to dicoumarol by molds that invade plants that are improperly cured or in molded silage • dicoumarol is competitive inhibitor of vitamin K epoxide reductase so interferes with production of clotting factors • cattle most often poisoned d.t. exposure M. alba Clinical signs • acute blood loss, subcutaneous hematomata, anemia, epistaxis, hemorrhagic diarrhea, abortion form placental hemorrhage Treatment • transfusion, phytonadione (vitamin K1)

30. Methemoglobinemia from nitrate-containing plants -1 • plants use nitrite to form vegetable protein from nitrate through action of nitrate reductase • nitrates accumulate in stalks and leaves • factors affecting nitrate accumulation in plants • nitrate, ammonia supply • moisture needed for uptake • acid soils favor absorption • (continued next page) Nitrate-containing plants: Amaranthus retroflexusZea mays (corn, maize) Avena sativa (oats) Chenopodium album Beta vulgaris (beets) Sorghum

31. Methemoglobinemia from nitrate-containing plants -2 • factors affecting nitrate accumulation in plants, cont’d. • nitrate reductase activity • need molybdenum, sulfur, phosphorus, adequate light • frost damage interferes for several days • drought reduces activity • phenoxy acetic herbicides increase growth rate and nitrate accumulation, highest 3-5 d post-application • plant species and phase - highest prior to flowering • ensiling reduces nitrate to nitrite and then ammonia

32. Methemoglobinemia from nitrate-containing plants - 3 • forage exceeding 1% nitrate may cause acute toxicosis • LD50 for cattle is 1g/kg • LD50 for ruminants is 0.5g/kg body weight • ruminants can adapt to higher nitrate [ ] with time • tolerance is increased by high-quality diet with readily available

33. Methemoglobinemia from nitrate-containing plants - 4 • nitrite ion oxidizes ferrous iron in hemoglobin to ferric state, forming methemoglobin, which is incapable of carrying oxygen • clinical toxicosis at 30-40%, death at 80-90% methemoglobin • results in abortion in pregnant females within 2-3 d as result of fetal death from anoxia

34. Methemoglobinemia from nitrate-containing plants - 5 • clinical signs • anxiety, polypnea, dyspnea, rapid, weak pulse • weakness, ataxia, low exercise intolerance • lab diagnosis • analysis of forage, hay, water for nitrates • methemoglobin [ ], must stabilize blood with phosphate buffer (1pt blood :20 pts buffer) • >30 ppm nitrate in ocular fluid diagnostic • lesions • dark brown blood staining of tissues, cyanosis

35. Methemoglobinemia from nitrate-containing plants - 6 • treatment • methylene blue, except in cats • may need to be repeated several times because nitrite continues to be formed in the rumen • large doses of antibiotics may inhibit ruminal reduction of nitrate to nitrite

36. Cyanide toxicosis - 1 • Factors influencing cyanide accumulation in plants • species • pitted fruits (peaches, apricots, cherries, almonds) • pome fruits (apples, pears) • grasses (Johnson, sorghums, corn) • elderberry • legumes (birdsfoot trefoil, white clover, vetch • portion of plant • cyanogenic glycosides [ ] in seeds, leaves, bark, stems, and fruit (in order from greatest to least)

37. Cyanide toxicosis - 2 • Factors influencing cyanide accumulation in plants - cont’d. • phase of plant growth • young rapidly growing plants or plants undergoing regrowth highest [ ] • environmental factors • stresses increase glycoside formation, damage to cell walls causes release of -glycosidase, which liberates free cyanide • soil conditions: high N and low Phos favor • temp, light, soil pH through effect on growth

38. Cyanide toxicosis - 3 • cyanide combines w/iron in cytochrome oxidase, blocking cellular respiration • rhodanese naturally detoxifies if thiosulfate available • cyanide + thiosulfate + rhodanese -> thiocyanate -> excreted in urine • ruminants more susceptible because of -glycosidase in rumen

39. Cyanide toxicosis - 4 Diagnosis • Clinical signs • initial excitement, muscle tremors w/in 30 minutes of ingestion • blood and tissues cherry red (blood is oxygenated but can’t release oxygen to cells) • Polypnea, dyspnea, chronic convulsions, coma, death

40. Cyanide toxicosis - 5 Diagnosis • Laboratory • plants may be analyzed for cyanide • urinary thiocyanate elevated • picric acid-impregnated paper for qualitative test • Lesions • blood clots slowly or not at all • bitter almond smell exuded from rumen • subendocardial, subepicardial hemorrhages • abomasum, intestine congested, petechiae

41. Cyanide toxicosis - 6 Treatment • goal is to break cyanide - cytochrome oxidase bond • sodium nitrite plus thiosulfate • sodium nitrite causes cyanmethemoglobin to form, releasing bond • thiosulfate assists natural detoxification • cobalt salts recommended but generally not used

42. Plants that affect reproduction Abortion Clinical estrogenism Teratogenic effects Agalactia

43. Pinus ponderosa (Western yellow pine, ponderosa pine), P. taeda (loblolly pine) • P. ponderosa, NW mtns. of U.S. • P. taeda, E and SE U.S. • unidentified agent in fresh and dried needles • causes abortion in cattle after substantial intake for several days Clinical signs • abortion in the last trimester of pregnancy • often edema of the udder and vulva in dam • retained placentas and metritis

44. Xanthocephalum(Western broomweed) • SW U.S. Texas to California to Idaho • saponin • ruminants, swine, rabbits are susceptible Clinical signs • acute • depression anorexia, nasal discharge, diarrhea • chronic • abortion in cattle in the first 2/3 of gestation • aborted calves are small • dam usually has a retained placenta

45. Trifolium repens (subterranean clover), T. subterraneum, Medicago sativa (alfalfa) • isofalvone estrogens genistein and formononetin cause signs related to Trifolium • coumestrol produced by alfalfa is moderately estrogenic Clinical signs • reduced transport and fertility of ova • cystic hyperplasia of the cervix • feminization • reduced libido in males

46. Teratogenic effects • Table in Osweiler

47. Agalactia • Claviceps purpurea (ergot) • Festuca arundinacea (Kentucky 31 tall fescue)

48. Plants that affect the skin Primary photosensitization Physical damage

49. Primary photosensitization • occurs when photodynamic agent is • directly ingested (or injected) • absorbed through skin • produced by biotransformation • major effects in the skin, other organs usually spared • prompt removal of photosensitizer, supportive Rx often results in recovery with few sequelae

50. Primary photosensitization • Cymopterus watsonii (spring parsley) • desert AZ and Utah • xanthotoxin and begapten • Fagopyrun esculentum (buckwheat) • fagopyrin in both green and dry plant • Hypericum perforatum (St. Johnswort) • hypericin, red pigment • cattle more susceptible than sheep